Rituximab versus mitoxantrone: comparing effectiveness and safety in advanced relapsing multiple sclerosis.

BACKGROUND: Rituximab (RTX), a CD20 depleting agent, is a frequently used off-label treatment for multiple sclerosis (MS), while mitoxantrone (MTX) is approved, albeit rarely used for active relapsing MS (RMS). However, observational data comparing RTX and MTX effectiveness and safety are scarce. OBJECTIVE: We aimed to compare effectiveness and safety of MTX and RTX in patients with active RMS. METHODS: From combined retrospective clinical data of three MS centers, we selected patients who had received at least one infusion of RTX or MTX and had at least a 6-month clinical follow-up available. Treatment groups were compared by propensity score (PS)-adjusted regression and inverse PS-weighted generalized estimated equation models regarding disability progression, relapse activity, and adverse events (AEs). RESULTS: We included 292 RMS patients (mean age 41.8 years, 71.6% female) who received RTX (119 patients, mean age 36.8 years, 74.8% female) or MTX (173 patients mean age 45.3 years, 69.4% female). Using both PS methods, we did not find a significant effect favoring RTX or MTX treatment regarding the probability of disability worsening or relapse occurrence. However, RTX treatment was associated with a significantly lower probability of severe AEs and AEs. CONCLUSIONS: RTX shows comparable effectiveness but a favorable safety profile compared with MTX in active RMS.

Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis.

Background Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (QFLC), FLC index and FLC intrathecal fraction (FLCIF). Methods κ- and λ-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. QFLC was calculated as the ratio of CSF/serum FLC concentration, the FLC index as QFLC/albumin quotient and the percentage FLCIF by comparing QFLC to a previously empirically determined, albumin quotient-dependent reference limit. Results CSF FLC concentration, QFLC, FLC index and FLCIF of both the κ- and λ-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.

Month-of-birth-effect in multiple sclerosis in Austria.

BACKGROUND: The month-of-birth-effect (MoBE) describes the finding that multiple sclerosis (MS) patients seem to have been born significantly more frequently in spring, with a rise in May, and significantly less often in autumn and winter with the fewest births in November. OBJECTIVES: To analyse if the MoBE can also be found in the Austrian MS population, and if so, whether the pattern is similar to the reported pattern in Canada, United Kingdom, and some Scandinavian countries. METHODS: The data of 7886 MS patients in Austria were compared to all live births in Austria from 1940 to 2010, that is, 7.256545 data entries of the Austrian birth registry and analysed in detail. RESULTS: Patterns observed in our MS cohort were not different from patterns in the general population, even when stratifying for gender. However, the noticeable and partly significant ups and downs over the examined years did not follow the distinct specific pattern with highest birth rates in spring and lowest birth rates in autumn that has been described previously for countries above the 49th latitude. CONCLUSION: After correcting for month-of-birth patterns in the general Austrian population, there is no evidence for the previously described MoBE in Austrian MS patients.

Secondary dementia due to Lyme neuroborreliosis.

Dementia-like syndromes are rare manifestations of Lyme neuroborreliosis. The clinical patterns are summarized using our own cases and case reports from the literature, which were diagnosed as definite Lyme neuroborreliosis according to the European guidelines. The cases disclose signs of subcortical dementia that occur more rapidly than in patients suffering from primary dementia. Gait disturbances early in the disease course is another frequently observed characteristic feature. The response to 2-4 weeks of antibiotic treatment with ceftriaxone was excellent. There were no indications for a prolonged antibiotic treatment. It is essential to be aware of this manifestation of Lyme neuroborreliosis, because early antibiotic treatment will prevent permanent sequelae that may occur throughout the further course of the untreated disease.

Characterization of the binding pattern of human aquaporin-4 autoantibodies in patients with neuromyelitis optica spectrum disorders.

BACKGROUND: The discovery of a highly specific antibody against the aquaporin-4 (AQP4) water channel (AQP4-IgG) unified the spectrum of neuromyelitis optica spectrum disorders (NMOSD), which are considered to be antibody-mediated autoimmune diseases. The AQP4 water channel is located on astrocytic end-feet processes and consists of six transmembrane helical domains forming three extracellular loops A, C, and E in which defined amino acids were already proven to be critical for AQP4-IgG binding. However, the clinical relevance of these findings is unclear. Therefore, we have characterized the epitope specificity of AQP4-IgG-positive NMOSD patients. METHODS: We established a cell-based flow cytometry assay for the quantitative detection of AQP4-IgG-positive serum samples. Human embryonic kidney (HEK) cells were transiently transfected with an EmGFP-tagged AQP4-M23, AQP4-M1, or six AQP4-M23 extracellular loop mutants including two mutations in loop A (serial AA substitution, insertion of a myc-tag), two in loop C (N153Q, insertion of a myc-tag), and two in loop E (H230G, insertion of a myc-tag). Fourty-seven baseline and 49 follow-up serum samples and six paired cerebrospinal fluid (CSF) baseline samples of 47 AQP4-IgG-positive Austrian NMOSD patients were then tested for their binding capability to AQP4-M1 and AQP4-M23 isoforms and these six extracellular loop mutants. RESULTS: Overall, we could identify two broad patterns of antibody recognition based on differential sensitivity to mutations in extracellular loop A. Pattern A was characterized by reduced binding to the two mutations in loop A, whereas pattern B had only partial or no reduced binding to these mutations. These two patterns were not associated with significant differences in demographic and clinical parameters or serum titers in this retrospective study. Interestingly, we found a change of AQP4-IgG epitope recognition pattern in seven of 20 NMOSD patients with available follow-up samples. Moreover, we found different binding patterns in five of six paired CSF versus serum samples, with a predominance of pattern A in CSF. CONCLUSIONS: Our study demonstrates that AQP4-IgG in sera of NMOSD patients show distinct patterns of antibody recognition. The clinical and diagnostic relevance of these findings have to be addressed in prospective studies.

Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: A multicenter study.

BACKGROUND: Kappa free light chains (KFLCs) have been proposed as a diagnostic biomarker in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to validate the diagnostic accuracy of intrathecal KFLC synthesis in a multicenter study. METHODS: KFLCs were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of patients with CIS (n = 60), MS (n = 60) and other neurological diseases (n = 60) from four different MS centers. The upper normal limit for intrathecal KFLC concentrations depending on blood-CSF barrier function was previously calculated in a cohort of 420 control patients. RESULTS: Diagnostic sensitivity of intrathecal KFLC synthesis, IgG synthesis according to Reiber, IgG index and oligoclonal bands (OCBs) was 95%, 72%, 73% and 93% in patients with MS and 82%, 47%, 43% and 72% in patients with CIS. Specificity of intrathecal KFLC synthesis was 95% and 98% for all other measures. CONCLUSION: These findings further support the diagnostic value of intrathecal KFLC synthesis in CIS and MS patients and demonstrate a valid, easier and rater-independent alternative to OCB detection.

CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable?

BACKGROUND: To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration. METHODS: 28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study. RESULTS: There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability. CONCLUSIONS: Based on the findings of this study, we recommend that the concept of 'clinico-radiologico paradox' in multiple sclerosis be extended to CROP-'clinico-radiologico-ophthalmological paradox'. Furthermore, OCT data of MS patients should be interpreted with caution.

NMDA receptor antibodies: A rare association in inflammatory demyelinating diseases.

OBJECTIVES: To analyze the frequency of NMDA receptor (NMDAR) antibodies in patients with various inflammatory demyelinating diseases of the CNS and to determine their clinical correlates. METHODS: Retrospective case-control study from 2005 to 2014 with the detection of serum IgG antibodies to NMDAR, aquaporin-4, and myelin oligodendrocyte glycoprotein by recombinant live cell-based immunofluorescence assays. Fifty-one patients with acute disseminated encephalomyelitis, 41 with neuromyelitis optica spectrum disorders, 34 with clinically isolated syndrome, and 89 with multiple sclerosis (MS) were included. Due to a known association of NMDAR antibodies with seizures and behavioral symptoms, patients with those clinical manifestations were preferentially included and are therefore overrepresented in our cohort. Nine patients with NMDAR encephalitis, 94 patients with other neurologic diseases, and 48 healthy individuals were used as controls. RESULTS: NMDAR antibodies were found in all 9 patients with NMDAR encephalitis but in only 1 of 215 (0.5%) patients with inflammatory demyelination and in none of the controls. This patient had relapsing-remitting MS with NMDAR antibodies present at disease onset, with an increase in NMDAR antibody titer with the onset of psychiatric symptoms and cognitive deficits. CONCLUSION: In demyelinating disorders, NMDAR antibodies are uncommon, even in those with symptoms seen in NMDAR encephalitis.

Corrigendum: "High-Resolution Spectral Domain-Optical Coherence Tomography in Multiple Sclerosis, Part II - The Total Macular Volume. The First Follow-Up Study Over 2 Years".

[This corrects the article on p. 20 in vol. 5, PMID: 24605107.].

Reduction in serum aquaporin-4 antibody titers during development of a tumor-like brain lesion in a patient with neuromyelitis optica: a serum antibody-consuming effect?

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a "serum antibody-consuming effect" during lesion formation.